Model of Intraperitoneal Targeted α-Particle Therapy Shows That Posttherapy Cold-Antibody Boost Enhances Microtumor Radiation Dose and Treatable Tumor Sizes

Abstract

Intraperitoneally administered radiolabeled monoclonal antibodies (mAbs) have been tested in several clinical trials, often with promising results, but have never proven curative. We have previously presented simulations of clinically relevant amounts of intraperitonealY-mAbs for treatment of minimal disease and shown that such treatments are unlikely to eradicate microtumors. Our previous model simulated the kinetics of intraperitoneally infused radiolabeled mAbs in humans and showed the benefit of instead using α-emitters such as At. In the current work, we introduce penetration of mAbs into microtumors with radii of up to 400 μm. Calculations were performed using dynamic simulation software. To determine the radiation dose distribution in nonvascularized microtumors of various sizes after intraperitonealAt-radioimmunotherapy, we used an in-house-developed Monte Carlo program for microdosimetry. Our aim was to find methods that optimize the therapy for as wide a tumor size range as possible. Our results show that high-specific-activity radiolabeled mAbs that are bound to a tumor surface will penetrate slowly compared with the half-lives ofAt and shorter-lived radionuclides. The inner-core cells of tumors with radii exceeding 100 μm may therefore not be sufficiently irradiated. For lower specific activities, the penetration rate and dose distribution will be more favorable for such tumors, but the dose to smaller microtumors and single cells will be low. Our calculations show that the addition of a boost with unlabeled mAb 1-5 h after therapy results in sufficient absorbed doses both to single cells and throughout microtumors up to approximately 300 μm in radius. This finding should also hold for other high-affinity mAbs and short-lived α-emitters.

Penetrating the Barriers to Successful α-Radioimmunotherapy

“…In conclusion, whereas the use of short-half-life radioisotopes directly conjugated to intact antibodies with long circulation times has previously been considered incongruent, the study by Palm et al (5) suggests that a timed manipulation of the a-radioimmunotherapy-specific activity in vivo may present a way to maximize the effectiveness of this approach in treatment-resistant microtumors with minimal additional toxicity. Despite this advance, a-radioimmunotherapy remains unlikely to prove an effective monotherapy for large solid tumors, and establishing the precise role of a-radioimmunotherapy in a multimodal treatment plan needs to be prioritized.…”

“…An article by Palm et al (5) in the April issue of The Journal of Nuclear Medicine focused on the implementation of radioimmunotherapy with a-particle-emitting radionuclides (a-radioimmunotherapy). The rationale for the use of a-radioimmunotherapy is based principally on the greater cytotoxicity and shorter range of the a-particle than of the b-particle, resulting in increased antitumor efficacy combined with decreased normal-tissue toxicity.…”

“…In the study by Palm et al (5), a combined kinetic and dosimetric model is used to identify methods that maximize a-particle therapy for a larger tumor size range, based on short-range a-radioimmunotherapy with 211 At-MX35 (5). The model itself contains many parameters derived from the previous extensive clinical study of the intraperitoneal administration of 211 Atlabeled MX35 and fragments thereof, recognizing a cell-surface antigen expressed on 90% of human ovarian epithelial cancers (13,14).…”

“…This approach has proven effective, and is routinely used, for some b-radioimmunotherapy strategies (15)(16)(17). However, the study by Palm et al (5) revealed that overcoming the tumor penetration issue in this manner also reduces absorbed doses in correctly targeted microtumors (,50 mm in radius) to subtherapeutic levels, because of lowered absolute a-radioimmunotherapy uptake. Again, swings and roundabouts-improved penetration in larger lesions comes at the cost of lower total absorbed dose in the smaller ones.…”

“…As a result of these potential hurdles, whether actual or anticipated, the theory that some combination of aand b-radioimmunotherapy would produce an optimal response in patients with a spectrum of tumor sizes remains largely untested and certainty warrants a more detailed investigation as the availability of novel a-radioimmunotherapies increases over the coming years. The findings in the study by Palm et al (5) raise the intriguing possibility that the sequence of a-radioimmunotherapy followed by cold antibody and subsequent b-radioimmunotherapy may provide a route to incorporating all these elements to their maximal efficacy. Apropos to the swings and roundabouts, it would appear that the maximum recipient benefit and provider profit might be obtained by optimally combining the use of both inventions.…”